Major efforts are currently being made to decrease antibody size, because the full-size antibodies exhibit poor penetration into tissues, especially solid tumors, and also poor or absent binding to surface regions of some antigens that may suffer from steric hindrance and can only be accessed by molecules of smaller size. Such endeavors include the engineering of a variety of antibody fragments such as Fab, Fv, scFv, VH and VHH, and more new antibody fragment formats are under development. However, to date these antibody fragments have been of limited use in therapeutic applications, because they usually display greatly reduced half-lives compared to full-size IgG. Molecules are needed that specifically bind an antigen, but are small and have a long half-life.
The Fc domain increases the half-life of an IgG through its unique pH-dependent association with the neonatal Fc receptor (FcRn). After internalization, the Fc domain of IgG can bind to FcRn in the acidic environment of the endosome, so that the IgG is then cycled onto the cell surface and re-released into circulation. This biological system protects IgG from degradation and results in a long serum half-life. Fusions of an Fc domain and a therapeutic molecule have an extended half life. In addition, since the Fc fragment of IgG consists of a tightly packed homodimer, two therapeutic proteins are present in each molecule. Recently, monomeric Fc fusion proteins were generated in which a single active protein was fused to dimeric wild-type Fc. These smaller molecules have been shown to possess even extended half-lives compared with the dimeric version. However, the Fc domain is still relatively large (˜50 kD). A need remains for monomeric Fc domains that are much smaller in size, and can be used to produce small and stable antigen binding molecules.